Polyketides are a large class of natural products that includes many important antibiotic, antifungal, anticancer, and anti-helminthic compounds such as erythromycins, amphotericins, daunorubicins, and avermectins. Their synthesis proceeds by an ordered condensation of acyl esters to generate carbon chains of varying length, side chain, and reduction pattern that are differentially cyclized and subsequently modified to give the mature polyketides. For many polyketides, maturation includes the addition of one or more sugar residues to the cyclized carbon chain. The sugar residues are frequently critical to the biological activity of the mature polyketide.
Streptomyces and the closely related Saccharopolyspora genera are prodigious producers of polyketide metabolites. Because of the commercial significance of these compounds, a great amount of effort has been expended in the study of Streptomyces genetics. Consequently, much is known about Streptomyces and several cloning vectors exist for introducing DNA into these organisms.
Although many polyketides have been identified, there remains the need to obtain novel glycosylation modified (as defined herein) polyketide structures with enhanced properties. Current methods of obtaining such molecules include screening of biological samples and chemical modification of existing polyketides, both of which are costly and time consuming. Current screening methods are based on gross properties of the molecule, i.e. antibacterial, antifungal activity, etc., and both a priori knowledge of the structure of the molecules obtained or predetermination of enhanced properties are virtually impossible. Standard chemical modification of existing structures has been successfully employed, but is limited by the number of types of compounds obtainable. Furthermore, the poor yield of multistep chemical syntheses often limits the practicality of this approach. The following modifications to sugar residues bound to polyketides are particularly difficult or inefficient at the present time: change the stereochemistry of specific hydroxyl or methyl groups, change the oxidation state of specific hydroxyl groups, and deoxygenation of specific carbons. Accordingly, there exists a need to obtain molecules wherein such changes are specified and performed which would represent an improvement in the technology to produce altered glycosylation-modified polyketide molecules with predicted structure.
The present invention overcomes these problems by providing the genetic sequence of sugar biosynthesis genes involved in the biosynthesis of polyketide-associated sugars.